Domain Interplay Mediated by an Essential Disulfide Linkage Is Critical for the Activity and Secretion of the Metastasis-promoting Enzyme Autotaxin

Autotaxin or NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2) is a secreted lysophospholipase-D that promotes metastasis and tumor growth by its ability to generate lysophosphatidic acid. Considerable evidence suggests that inhibitors of NPP2 can be used as a novel therapy for the treatment of...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-05, Vol.284 (21), p.14296-14302
Main Authors: Jansen, Silvia, Andries, Maria, Derua, Rita, Waelkens, Etienne, Bollen, Mathieu
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biocatalysis - drug effects
Cell Line
Cysteine - metabolism
Disulfides - metabolism
Dithiothreitol - pharmacology
Endopeptidases - metabolism
Enzyme Activation - drug effects
Enzyme Catalysis and Regulation
Humans
Lysine - metabolism
Molecular Sequence Data
Neoplasm Metastasis - pathology
Phosphoric Diester Hydrolases - chemistry
Phosphoric Diester Hydrolases - metabolism
Protein Structure, Tertiary
Pyrophosphatases - chemistry
Pyrophosphatases - metabolism
Rats
Structure-Activity Relationship
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Summary:Autotaxin or NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2) is a secreted lysophospholipase-D that promotes metastasis and tumor growth by its ability to generate lysophosphatidic acid. Considerable evidence suggests that inhibitors of NPP2 can be used as a novel therapy for the treatment of cancer. Although most attention is currently directed toward the development of inhibitors of the catalytic site, we have explored whether NPP2 can also be targeted through its non-catalytic nuclease-like domain. We demonstrate here that the catalytic and nuclease-like domains are covalently linked by an essential disulfide bridge between Cys413 and Cys805. Within the nuclease-like domain, residues 829–850 are involved in the secretion of NPP2, and Lys852 is required for the expression of catalytic activity. These data show that the nuclease-like domain is crucial for catalysis by NPP2 and is a possible target to generate inhibitors.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M900790200